The central hypothesis of this proposal is that abnormal beat-to-beat fluctuations in ventricular repolarization occur in close association with malignant arrhythmias and that quantification of these fluctuations provides a noninvasive measure of electrical instability. The proposed studies will make use of an automated technique to measure subtle beat-to-beat QT interval variability (QTV) from the surface electrocardiogram. Physiologic QTV in normal dogs and normal human volunteers will be quantified, and the relationship between normal heart rate variability and QTV will be established. The effect of dilated cardiomyopathy (DCM) on QTV will then be examined both in an established dog model of DCM and in patients with DCM. Two fundamental issues regarding the underlying mechanisms of QTV will be addressed. First, is increased QTV with DCM due to diffuse or localized repolarization lability? To answer this question, spatially disparate data will be acquired invasively in dogs with monophasic action potential recordings obtained at multiple endocardial sites, and noninvasively in humans by use of 12 simultaneous surface ECG leads. Second, is QTV mediated by the autonomic nervous system? QTV will be measured both in patients with DCM and those with structurally normal hearts undergoing electrophysiologic study, during sinus rhythm and during atrial pacing, before and after pharmacologic autonomic blockade, to test the hypothesis that QTV is autonomically mediated in the absence of structural heart disease but becomes decoupled from autonomic control in DCM. The final set of proposed studies are designed to test the effect of acute metabolic abnormalities on the QTV. The QTV will be measured in dogs with DCM during progressive hypokalemia, and in humans undergoing percutaneous transluminal coronary angioplasty (PTCA) during ischemia induced by balloon inflation. These studies will test the hypothesis that repolarization lability accompanies and may herald the onset of malignant ventricular arrhythmias brought about by an abnormal metabolic state.